EphA5 and ephrin-A2 expression during optic nerve regeneration: a 'two-edged sword'

During development, gradients of EphA receptors (nasallow–temporalhigh) and their ligands ephrin‐As (rostrallow–caudalhigh) are involved in establishing topography between retinal ganglion cells (RGCs) and the superior colliculus (SC). EphA5‐expressing RGC axons are repulsed by ephrin‐A2‐expressing SC neurones. In adult rats RGCs maintain graded EphA5 expression but ephrin‐A2 expression is down‐regulated in the SC to a weak gradient. At 1 month after optic nerve transection, EphA5 expression is reduced in the few remaining RGCs and is no longer graded; by contrast, SC ephrin‐A2 is up‐regulated to a rostrallow–caudalhigh gradient. Here we examined expression in adult rat 1 month after bridging the retina and SC with a peripheral nerve graft, a procedure that enhances RGC survival and permits RGC axon regeneration. Double labelling with cell markers revealed preservation of a nasallow–temporalhigh EphA5 gradient in RGCs and establishment of a rostrallow–caudalhigh ephrin‐A2 gradient within neurones of the SC. The results suggest a potential for guidance cues to restore the topography of RGC axons in the SC. However, high ephrin‐A2 levels were also found in astrocytes surrounding the peripheral nerve graft insertion site. The repulsive ephrin‐A2 environment offers at least a partial explanation for the observation that only a limited number of RGC axons can exit the graft to enter target central nervous system tissue.